Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.
GP73 closely correlated with exosome biogenesis and CRC liver metastasis, and GP73 blockade may merit exploration as a potential therapeutic strategy for mitigating CRC liver metastasis.
Keywords: Colorectal cancer; Exosome; Golgi protein 73; Metastasis.
© 2025. The Author(s).